To define the mechanism(s) by which fructose may contribute to nonalcoholic fatty liver disease (NAFLD) progression and assess whether such factors can be measured using magnetic resonance (MR) biomarkers and modified with dietary fructose restriction. Background: NAFLD is a major public health concern which is anticipated to surpass the morbidity and mortality of other forms of chronic liver disease by 2020. Both the prevalence and severity of NAFLD have been associated with increased consumption of fructose. We have reported that increased fructose consumption is associated with decreased hepatic steatosis, liver injury (necroinflammation and hepatocyte ballooning) and fibrosis in a dose-dependent manner. The unique metabolism of fructose, one which depletes hepatic ATP, increases uric acid, and worsens features of insulin resistance, is a potential mechanism that may account for fructose-related liver injury in NAFLD. Given the changes which occur with fructose exposure, fructose is an ideal diagnostic tool by which to induce and/or amplify changes in quantitative MR-based biomarkers and target for dietary intervention studies for the treatment of NAFLD. Hypothesis: We hypothesize that fructose is a risk factor for hepatic steatosis, steatohepatitis, and advanced fibrosis and that acute and chronic fructose exposure will worsen the metabolic, energy homeostatic and associated MR-based biomarkers features of NAFLD. Further, we hypothesize that dietary fructose restriction will improve these metabolic and energy homeostatic derangements. Approach: Quantitative MR biomarkers of hepatic metabolites and energy homeostasis will be evaluated before, during, and after acute/chronic fructose challenges. We will characterize the pathophysiologic changes which occur with fructose exposure using multi-parametric analysis of MRI and 1H and 31P and spectroscopic imaging data to measures of metabolism and energy homeostasis and relate these to the histologic features of NAFLD. Impact: This work addresses the following significant gaps in knowledge: 1) whether acute and chronic fructose exposure alters metabolism, energy homeostasis, and is associated with liver injury in patients with/without NAFLD and 2) whether modification of fructose consumption could improve the clinical and pathologic features of NAFLD. The successful completion of the proposed studies will provide novel and clinically relevant information regarding the pathophysiologic and pathologic mechanism underlying fructose-related liver injury in humans. The proposed studies will be the first to correlate the dynamic measures of non-invasive MR-based biomarkers and energy homeostasis with the clinical, metabolic and histologic features of NAFLD. The integration of these biomarkers in a cross-sectional and longitudinal study will characterize their use for measuring changes associated with fructose-related liver injury and facilitate the development of non-invasive biomarkers for NAFLD diagnosis and progression. PUBLIC HEALTH RELEVANCE: The goal of this project is to define the mechanism(s) by which fructose may contribute to nonalcoholic fatty liver disease (NAFLD) progression, assess whether such factors can be measured using dynamic MRI/MRS biomarkers and whether these factors can be modified with dietary fructose restriction.